EP1102581B1 - A microemulsion forming composition for the sustained release of an active agent - Google Patents

Abstract

The invention concerns a composition comprising a microemulsion forming system by contact with a hydrophilic phase brought, after ingestion, by the physiological fluid, said microemulsion forming system comprising: at least an active principle; a lipophilic phase; a surfactant (TA); a co-surfactant (CoTA) . The invention is characterized in that said composition further comprises an inert polymeric matrix which cannot be ionised at physiological pH, dispersed in the microemulsion forming system before ingestion, said polymeric matrix being capable, after ingestion, of forming on contacting the physiological fluid, a gelled polymeric matrix enabling to release by diffusion, in continuous and prolonged manner the already microemulsified active principle.

Description

The invention relates to a principle sustained release composition. active administered in particular orally, for pharmaceutical use or cosmetic, capable of forming a microemulsion with an external hydrophilic phase, for example physiological fluid or water, while gradually releasing the asset it contains in situ. It also relates to the manufacturing process of said composition.

As we know, a microemulsion is a homogeneous, fluid solution and stable, consisting of four major constituents respectively a phase hydrophilic, a lipophilic phase, at least one surfactant (TA) and at least a cotensioactive agent. Microemulsions are distinguished from emulsions and micellar solutions in particular by the size of the droplets of which they are formed. Indeed, the size of the droplets of a microemulsion is understood between 10 and 200 nanometers (nm) while it is less than 10 nm for a micellar solution and greater than 200 nm for an emulsion. Furthermore, at the difference of the emulsions, which are unstable, the micro-emulsions, which necessarily include a cosurfactant, are stable. In addition, we characterizes a microemulsion by its more or less accentuated transparency due the proportion of reflected light transmitted by a light beam, the intensity of the light beam having crossed being less than that of the incident beam. The reflected light being richer in blue and purple radiations, microemulsions finely scattered take on a bluish appearance. This is the effect said TYNDALL describes in particular in the book "Emulsions, micro-emulsions, multiple emulsions ”by Jean Poré.

• un actif,
• une phase lipophile constituée d'un mélange de mono-, di- et triglycérides et des acides gras en C₈-C₁₈ et de mono- et diesters de polyéthylène glycol présentant une balance hydrophile/lipophile (HLB) inférieure à 16 ;
• un agent tensio-actif (TA) à base de glycérides présentant une HLB inférieure à 16 choisi dans le groupe comprenant les glycérides polyglycolysés saturés en C₈-C₁₀ et les esters oléïques du polyglycérol ;
• un agent cotensio-actif (CoTA) choisi dans le groupe comprenant les esters lauriques du propylène glycol, les esters oléïques du polyglycérol, l'éthyl diglycol et le polyéthylène glycol ;
• le rapport TA-CoTA étant compris entre 0,5 et 6.

The Applicant has described in document EP-A-0 670 715 a composition formed of a self-micro-emulsifying active agent vector system known under the British expression SMEDDS®, trademark registered by the Applicant meaning Self Micro Emulsifying Drug Delivery System. These systems are described at length in the above-mentioned document and essentially include:

• active,
• a lipophilic phase consisting of a mixture of mono-, di- and triglycerides and C ₈ -C ₁₈ fatty acids and polyethylene glycol mono- and diesters having a hydrophilic / lipophilic balance (HLB) of less than 16;
• a surfactant (TA) based on glycerides having an HLB of less than 16 chosen from the group comprising polyglycolysed saturated C ₈ -C ₁₀ glycerides and oleic esters of polyglycerol;
• a cosurfactant (CoTA) selected from the group comprising lauric esters of propylene glycol, oleic esters of polyglycerol, ethyl diglycol and polyethylene glycol;
• the TA-CoTA ratio being between 0.5 and 6.

Certain products marketed by the Applicant, consisting of acids saturated and / or unsaturated fats and esters of these fatty acids, can be used in as a lipophilic phase, surfactant and co-surfactant, such as by example the association respectively of GELUCIRE 44/14, LABRAFAC CM10 and LAUROGLYCOL described in examples 1 and 2 of the above-mentioned document.

SMEDDS® can be presented at room temperature in the form solid or liquid, depending on the very nature of the fatty substances that compose them. Thus, if at least one of the fatty substances constituting SMEDDS® has a point of melting above room temperature (around 25 ° C) then the SMEDDS® will be semi-solid at room temperature. On the contrary, if at least one fatty substance constituent of SMEDDS® has a melting point below about 25 ° C, then the SMEDDS® is liquid at room temperature.

Consequently, SMEDDS® can be incorporated into capsules with liquid state, possibly hot, then, depending on the nature of their constituents, remain liquid or become semi-solid at room temperature.

Due to the formation of the micro-emulsion in situ, the SMEDDS® solubilize the active ingredient and therefore increase the bioavailability of the micro-emulsified active ingredient (s) they carry. However, the formation of the microemulsion gives the composition characteristics of immediate release of micro-emulsified active ingredient.

WO 96/21439 describes a pharmaceutical composition for the treatment of hyperlipidemia comprising a mixture of fenofibrate, polyglycosylated glycerides (in particular GELUCIRE® 44/14) and derivatives of cellulose or polyoxamers. In this document, cellulose derivatives are used as stabilizers, preventing the formation of crystals fenofibrate during cooling of the hard capsule.

Document EP-A-0 222 614 describes a combination of GELUCIRE® 46/07 marketed by GATTEFOSSE and a hydrophilic agent. The GELUCIRE® 46/07 cannot be considered as a SMEDDS®, insofar as where it contains in particular no cotensio-active phase, such as esters of propylene glycol, oleic ester of polyglycerol or ethyl diglycol.

Document EP-A-806 202 describes the use of a stabilizing agent for hydroxypropyl methyl cellulose type in a lipophilic matrix, the kinetics of which release of the active ingredient is, due to the erosion of said matrix, more or less regular. This document therefore does not concern a composition liable to create an emulsion and even less a microemulsion but a matrix lipid releasing the active ingredient by erosion.

Document US-A-5 206 219 describes a pharmaceutical composition for base of active ingredient capable of forming a microemulsion in situ in the intestinal tract. The composition described comprises, as the liphilic phase, phospholipids and not polyglycosylated glycerides and surfactants with high HLB, close to 18, leading to the formation of true emulsions and not microemulsions.

In other words, the problem which the invention proposes to solve is to provide a composition of the SMEDDS® type capable of gradually releasing the or the assets that it carries, regardless of the consistency of SMEDDS® at room temperature, solid or liquid.

• au moins un actif,
• une phase lipophile constituée d'un mélange de mono-, di- et triglycérides et des acides gras en C₈-C₁₈ et de mono- et diesters de polyéthylène glycol présentant une balance hydrophile/lipophile (HLB) inférieure à 16;
• un agent tensio-actif (TA) à base de glycérides présentant une HLB inférieure à 16 choisi dans le groupe comprenant les glycérides polyglycolysés saturés en C₈-C₁₀ et les esters oléïques du polyglycérol ;
• un agent cotensio-actif (CoTA) choisi dans le groupe comprenant les esters d'acides gras du propylène glycol, les esters oléïques du polyglycérol, l'éthyl diglycol ;
• le rapport TA-CoTA étant compris entre 0,5 et 6.

To solve this problem, the invention provides a composition for prolonged release of the active principle for pharmaceutical or cosmetic use intended to be ingested comprising a self-micro-emulsifiable system in contact with a hydrophilic phase provided, after ingestion, by the physiological liquid. , said self-emulsifiable system comprising:

• at least one asset,
• a lipophilic phase consisting of a mixture of mono-, di- and triglycerides and C ₈ -C ₁₈ fatty acids and polyethylene glycol mono- and diesters having a hydrophilic / lipophilic balance (HLB) of less than 16;
• a surfactant (TA) based on glycerides having an HLB of less than 16 chosen from the group comprising polyglycolysed saturated C ₈ -C ₁₀ glycerides and oleic esters of polyglycerol;
• a cosurfactant (CoTA) selected from the group comprising fatty acid esters of propylene glycol, oleic esters of polyglycerol, ethyl diglycol;
• the TA-CoTA ratio being between 0.5 and 6.

The composition of the invention is characterized in that it further comprises an inert non-ionizable polymeric matrix at physiological pH, dispersed in the auto-microemulsion system before ingestion, said polymeric matrix being able, after ingestion, to form, in contact with the physiological liquid, a gelled polymer matrix making it possible to release by diffusion, in a continuous and prolonged manner, the active then microemulsified.

In the following description and in the claims, by “micro-emulsified active ingredient”, we designate the active solubilized at the heart of the microemulsion, that is to say in its hydrophobic zone.

Similarly, by the expression "physiological liquid", we mean the medium physiological in vivo, as it appears after ingestion of the composition and whose pH will vary depending on the condition of the gastrointestinal tract.

However, at the experimental stage, i.e. without ingestion of the composition, the physiological fluid is replaced by water or a medium physiological in vitro reconstituted. In this case, the microemulsion will form on simple contact of the aqueous phase.

In the following description and in the claims, by the expression "polyglycolysed glycerides" means a mixture of mono-, di- and triglycerides and polyethylene glycol (PEG) mono- and diesters of molecular weight included preferably between 200 and 600, optionally glycerol and free PEG, of which adjust the HLB value by length of the PEG chain and whose point of adjustment fusion by the length of the chains of fatty acids, PEG and degrees of saturation of fatty chains, therefore of the starting oil.

Similarly, by the expression "fatty acids C ₈ to C ₁₈ ", which is also written C ₈ -C ₁₈ , is meant mixtures in significant and variable proportions of caprylic acids (C ₈ ), capric (C ₁₀ ), lauric (C ₁₂ ), myristic (C ₁₄ ), palmitic (C ₁₆ ) and stearic (C ₁₈ ), when these acids are saturated and the corresponding unsaturated acids in C ₈ -C ₁₈ .

It is recalled that the proportions of these fatty acids can vary in function of the starting oils.

In a preferred embodiment of the invention, the cotensio agent active ingredient is chosen from the group comprising lauric esters of propylene glycol, the capric esters of propylene glycol and the palmitic esters of propylene glycol.

In other words, the invention consists in incorporating a matrix inert polymer within a self-micro-emulsifiable system. Said system self-microemulsion then forms a microemulsion after ingestion, at contact of physiological fluid, thus allowing by diffusion through the matrix then gelled on contact with physiological fluid to gradually release from continuously and regularly the micro-emulsified active ingredient (s).

In practice, when the composition of the invention is formulated in capsules, after ingestion, the capsule dissolves on contact with digestive fluids, causing in parallel the formation of a small fraction of microemulsion, since the water gradually comes into contact with SMEDDS®. It follows that a small part of the active ingredient is then microemulsified, then the active ingredient microemulsified released.

Concomitantly, the polymer will gradually hydrate, then gel, thus causing the formation of a viscous layer, the volume of which will gradually increase to form a matrix from which the microemulsion is released by broadcast. The gelled barrier thus formed opposes therefore with the rapid release of the micro-emulsified active principle and by controlling the water penetration from the outside to the inside, gradually releases said micro-emulsified active ingredient.

In addition, in the case where the SMEDDS® includes fatty substances of HLB> 10, it was found that quite surprisingly the matrix polymer is gelified only after ingestion, i.e. in contact with physiological fluid, when one would have expected gelation occurs before ingestion on contact with the SMEDDS® components, including very high HLB value (> 10) could have caused the solvation of the polymer, and thus lead to the formation of a gel.

In addition, it was not clear that the asset release rate did not fluctuate as a function of hydrodynamic conditions, i.e. as a function of motility intestinal, in particular by erosion of the matrix, as occurs for monolithic systems. On the contrary, the composition according to the invention has the advantage of being independent of hydrodynamic conditions, since the matrix on contact with physiological fluid swells and forms a continuous network, allowing to release the micelles constituting the microemulsion.

In a first embodiment of the invention, so that the matrix polymer forms a hydrated network and therefore a gel in contact with the liquid physiological, the polymer matrix is chosen from the group comprising cellulosic polymers.

According to this embodiment, the polymer matrix has a weight molecular less than a million.

For a molecular weight greater than one million, the viscosity of the composition is too high and the release of SMEDDS® is improved

Advantageously, the molecular weight of the polymer matrix is between 80,000 and 800,000.

In a second embodiment of the invention, the matrix polymer is selected from the group comprising acrylic polymers. All acrylic polymers capable of swelling on contact with an aqueous phase may agree.

In a third embodiment of the invention, the matrix polymer is chosen from the group comprising non-polysaccharides cellulosics, for example gums.

When it is desired to incorporate a hydrophobic active ingredient into SMEDDS®, uses a hydrophilic polymer matrix chosen from the group including hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methylcellulose alone or as a mixture.

Similarly, when it is desired to incorporate a hydrophilic active ingredient in the SMEDDS®, a hydrophobic polymeric matrix of the ethyl type is used cellulose.

The composition of the invention thus makes it possible to use active agents hydrophilic regardless of their water solubility, since the release of the asset is not produced according to its water solubility, but by diffusion of micelles, the active ingredient being previously presented in a form of SMEDDS®.

To cause gelation of the polymer matrix in contact with physiological fluid, while ensuring the formation of the microemulsion, the inert polymer matrix represents from 0.5 to 40% by weight of the composition total.

For a concentration of less than 0.5%, no gelation is observed of the matrix in contact with physiological fluid. On the contrary, for a matrix concentration greater than 40%, the solution becomes too viscous.

Advantageously, the concentration of polymer matrix is understood between 5 and 25% by weight of the total composition.

The invention also relates to the method for manufacturing the composition.

• on prépare tout d'abord un système auto-micro-émulsionable en mélangeant, le cas échéant tout en chauffant, sous agitation, l'actif, la phase lipophile, l'agent tensio-actif et l'agent cotensio-actif ;
• puis, toujours sous agitation, on disperse progressivement la matrice polymérique sous forme de poudre au sein dudit système auto-micro-émulsionable.

According to this process:

• first of all, a self-emulsifiable system is prepared by mixing, if necessary while heating, with stirring, the active agent, the lipophilic phase, the surfactant and the cosurfactant;
• then, still with stirring, the polymer matrix is gradually dispersed in the form of powder within said self-micro-emulsifiable system.

The composition of the invention, which at room temperature, is in the state liquid or semi-solid depending on the nature of the SMEDDS® constituents, will formulated as a capsule.

In this case, these will be filled with the composition of the invention at the liquid state, possibly previously heated, which during cooling and depending on the composition of SMEDDS® may solidify at room temperature.

The invention therefore also relates to the capsule incorporating SMEDDS® into extended release described above.

The invention and the advantages which ensue therefrom will emerge more clearly from the following embodiment using the appended figures.

Figure 1 is a schematic representation of the release system the active from the composition of the invention.

Figure 2 is a representation of the dissolution curves indomethacin at pH 1.2 for indomethacin alone, indomethacin formulated under form of SMEDDS® as described in document EP-A-0 670 715 and indometacin formulated in the form of SMEDDS® prolonged release such as described in the present invention.

Example 1

As already said, Figure 1 shows how the matrix works polymer dispersed in a SMEDDS® type formula, the composition obtained in the form of a capsule.

In Figure 1a, there is shown a capsule (1) containing a matrix polymer (2) homogeneously distributed in the dry state in the mass and a auto-micro emulsifiable system (3) or SMEDDS®.

As shown in Figure 1b, in contact with the hydrophilic phase, that is to say physiological fluid, the capsule (1) is dissolved, allowing the fluid physiological to enter the mixture of polymer and SMEDDS®.

On contact with water, the polymer matrix gradually forms structuring a gelled barrier (4).

As shown in Figure 1c, the polymer matrix deconstructs gradually allowing the SMEDDS® to be released slowly.

Example 2

The following test was carried out in the laboratory using water as a physiological medium.

- Manufacture of the composition of the invention in the form of a capsule

In this example, a SMEDDS® is prepared, the composition of which is as follows: surfactant Labrasol 43.40% cosurfactant PLUROLOLEIQUE 14.40% lipophilic phase LABRAFIL WL2609BS 38.40% active ingredient indomethacin 4%.

In known manner, the constituents of SMEDDS® are mixed with room temperature with stirring between 60 and 100 revolutions per minute.

The matrix is then gradually dispersed, still with stirring. polymer composed of Hydroxypropylmethylcellulose (HPMC) representing 20% of the final composition.

A liquid preparation is obtained which is then formulated in capsules.

- Dissolution curves

FIG. 2 shows the dissolution curves of indomethacin when the active ingredient is alone (curve 1), is in the form of SMEDDS® immediate release (curve 2), or comes in the form of SMEDDS® extended release according to the invention (curve 3).

As this figure shows, indomethacin which we know is insoluble at acidic pH (curve 3), can be made perfectly available when incorporated into a SMEDDS® (curve 1 and 2).

As curve 2 shows, the composition of the invention exhibits extended release characteristics despite the fact that SMEDDS® is present in liquid state at room temperature.

- Characterization of the microemulsion formed by the composition of the invention TYNDALL effect

The microemulsion obtained in vitro has a bluish appearance which corresponds to the TYNDALL effect.

Size of the droplets forming the microemulsion

The size of the photons was measured by photon correlation spectroscopy. droplets of the microemulsion obtained in vitro when the composition of the invention is brought into contact with an aqueous phase.

The average droplet size obtained is 25 nanometers.

The advantages of the invention appear clearly from the description above.

Note in particular the possibility of incorporating SMEDDS® within sustained release forms to increase the bioavailability of the asset.

It is also noted that quite surprisingly, the composition of the invention has a structure such that it gradually releases the active ingredient in vivo, even if SMEDDS® is in liquid form at room temperature.

Claims (12)

1. Composition intended to be ingested, comprising a system which is self-microemulsifying on contact with a hydrophilic phase provided, after ingestion, by the physiological fluid, the said self-microemulsifying system comprising:

   at least one active agent,

   a lipophilic phase consisting of a mixture of mono-, di- and triglycerides and of C₈-C₁₈ fatty acids and of polyethylene glycol monoesters and diesters with a hydrophilic/lipophilic balance (HLB) of less than 16;

   a glyceride-based surfactant (SA) with an HLB of less than 16, chosen from the group comprising saturated C₈-C₁₀ polyglycosylated glycerides and oleic esters of polyglycerol;

   a co-surfactant (CoSA) chosen from the group comprising fatty acid esters of propylene glycol, oleic esters of polyglycerol, and ethyl diglycol;

   the SA-CoSA ratio being between 0.5 and 6;

   characterized in that the said composition also comprises an inert polymer matrix, representing from 0.5% to 40% relative to the weight of the total composition, which is not ionizable at physiological pH, dispersed in the self-microemulsifying system before ingestion, the said polymer matrix being capable, after ingestion, of forming, in contact with physiological fluid, a gelled polymer matrix making it possible to release the thus microemulsified active agent in a continuous and sustained manner by diffusion.
2. Composition according to Claim 1, characterized in that the co-surfactant is chosen from the group comprising lauric esters of propylene glycol, capric esters of propylene glycol and palmitic esters of propylene glycol.
3. Composition according to either of the preceding claims, characterized in that the polymer matrix is chosen from the group comprising cellulose polymers.
4. Composition according to Claim 3, characterized in that the molecular weight of the polymer matrix is less than one million.
5. Composition according to Claim 4, characterized in that the molecular weight of the polymer matrix is between 80,000 and 800,000.
6. Composition according to one of Claims 2 to 5, characterized in that the polymer matrix is hydrophilic and chosen from the group comprising hydroxypropylcellulose, hydroxypropylmethylcellulose and methylcellulose, alone or as a mixture.
7. Composition according to one of Claims 2 to 5, characterized in that the polymer matrix is hydrophobic and consists of ethylcellulose.
8. Composition according to either of Claims 1 and 2, characterized in that the polymer matrix is chosen from the group comprising acrylic polymers which are capable of swelling on contact with an aqueous phase.
9. Composition according to either of Claims 1 and 2, characterized in that the polymer matrix is chosen from the group comprising non-cellulose polysaccharides.
10. Composition according to Claim 9, characterized in that the inert polymer matrix represents from 5% to 25% relative to the weight of the total composition.
11. Process for manufacturing the composition which is the subject of Claims 1 to 10, in which:

    a self-microemulsifying system is first prepared by mixing, if necessary while heating, with stirring, the active agent, a lipophilic phase, a surfactant and a co-surfactant;

    the polymer matrix in powder form is then gradually dispersed, while still stirring, in the said self-microemulsifying system.
12. Gel capsule incorporating the composition which is the subject of one of Claims 1 to 10.

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